1. Field of Invention
The present invention relates to retroviral protease inhibitors and, more particularly relates to novel compounds and a composition and method for inhibiting retroviral proteases. This invention, in particular, relates to N-heterocyclic moiety containing hydroxyethylamine protease inhibitor compounds, a composition and method for inhibiting retroviral proteases such as human immunodeficiency virus (HIV) protease and for treatment or prophylaxis of a retroviral infection, e.g., an HIV infection. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
2. Related Art
During the replication cycle of retroviruses, gag and gag-poll gene products are translated as proteins. These proteins are subsequently processed by a virally encoded protease (or proteinase) to yield viral enzymes and structural proteins of the virus core. Most commonly, the gag precursor proteins are processed into the core proteins and the poll precursor proteins are processed into the viral enzymes, e.g., reverse transcriptase and retroviral protease. It has been shown that correct processing of the precursor proteins by the retroviral protease is necessary for assembly of infectious virons. For example, it has been shown that frameshift mutations in the protease region of the poll gene of HIV prevents processing of the gag precursor protein. It has also been shown through site-directed mutagenesis of an aspartic acid residue in the HIV protease that processing of the gag precursor protein is prevented. Thus, attempts have been made to inhibit viral replication by inhibiting the action of retroviral proteases.
Retroviral protease inhibition typically involves a transition state mimetic whereby the retroviral protease is exposed to a mimetic compound which binds (typically in a reversible manner) to the enzyme in competition with the gag and gag-poll proteins to thereby inhibit replication of structural proteins and, more importantly, the retroviral protease itself. In this manner, retroviral proteases can be effectively inhibited.
Several classes of mimetic compounds are known to be useful as inhibitors of the proteolytic enzyme renin. See, for example, U.S. Pat. No. 4,599,198; G.B. 2,184,730; G.B. 2,209,752; EP 0 264 795; G.B. 2,200,115 and U.S. SIR H725. Of these, G.B. 2,200,115; G.B 2,209,752; EP 0 264,795; U.S. SIR H725; and U.S. Pat. No. 4,599,198 disclose urea containing hydroxyethylamine renin inhibitors.
However, it is known that, although renin and HIV proteases are both classified as aspartyl proteases, compounds which are effective renin inhibitors generally cannot be predicted to be effective HIV protease inhibitors.
Several classes of mimetic compounds have been proposed, particularly for inhibition of proteases, such as for inhibition of HIV protease. Such mimetics include hydroxyethylamine isoteres and reduced amide isosteres. See, for example, EP 0 346 847; EP 0 342,541; Roberts et al, xe2x80x9cRational Design of Peptide Based Proteinase Inhibitors, xe2x80x9cScience, 248, 358 (1990); and Erickson et al,xe2x80x9d Design, Activity, and 2.8A Crystal Structure of a C2 Symmetric Inhibitor Complexed to HIV-1 Protease,xe2x80x9d Science, 249, 527 (1990). EP 0 346 847 and U.S. Pat. No. 5,648,364 disclose certain N-heterocyclic moiety-containing hydroxyethylamine protease inhibitor compounds, but do not suggest or disclose those of the present invention. WO 95/09843, WO 96/28464, U.S. Pat. No. 5,484,926, U.S. Pat. No. 5,705,500, U.S. Pat. No. 5,756,533, U.S. Pat. No. 5,776,971 and Kaldor, Stephen W., xe2x80x9cA systematic Study of P1-P3 Spanning Sidechains for the Inhibition of HIV-1 Proteasexe2x80x9d, Bioorganic and Medicinal Chemistry Letters, 5, 715-720 (1995) disclose arylthiol containing hydroxyethylamine isosteres incorporated into HIV-protease inhibitors but do not suggest or disclose the compounds of the present invention.
While it has been suggested that no improvement in the in vitro or ex vivo potency of hydroxyethylamine based inhibitors of HIV-protease containing a P2 asparagine can be made (Science, Roberts et al.), this is not the case. Improvements over P2 asparagine containing inhibitors are made. The moieties reported herein are expected to permit certain allowances over the aforementioned reference including proteolytic stability, duration of action in vivo and pharmacokinetic profile.
The present invention is directed to virus inhibiting compounds and compositions. More particularly, the present invention is directed to retroviral protease inhibiting compounds and compositions, to a method of inhibiting retroviral proteases, to processes for preparing the compounds and to intermediates useful in such processes. The subject compounds are characterized as N-heterocyclic moiety containing hydroxyethylamine inhibitor compounds.
In accordance with the present invention, there are provided several novel retroviral protease inhibiting compounds or a pharmaceutically acceptable salt, prodrug or ester thereof.
A preferred class of retroviral inhibitor compounds of the present invention are those represented by the formula: 
or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein:
R represents hydrogen, alkoxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbanoyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocycloxycarbonyl, heteroaralkoxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aralkylaminoalkylcarbonyl, aminoalkanoyl, aminocarbonyl, aminocarbonylalkyl, alkylaminoalkylcarbonyl, and mono- and disubstituted aminocarbonyl and aminoalkanoyl radicals wherein the substituents are selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, alkoxycarbonyl, arylalkyloxycarbonyl and heterocycloalkylalkyl radicals, or in the case of disubstituted aminoalkanoyl, said substituents along with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl radical;
Rxe2x80x2 represents radicals defined for R3 or R and Rxe2x80x2 together with the nitrogen to which they are attached form a heterocycloalkyl or heteroaryl radical;
R1 represents hydrogen, xe2x80x94CH2SO2NH2, xe2x80x94CO2CH3, xe2x80x94CH2CO2CH3, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, xe2x80x94C(O)N(CH3)2, xe2x80x94CH2C(O)NHCH3, xe2x80x94CH2C(O)N(CH3)2, alkyl, alkylthioalkyl, thiolalkyl and the corresponding sulfoxide and sulfone derivatives thereof, alkenyl, alkynyl, haloalkyl, alkoxyalkyl and cycloalkyl radicals and amino acid side chains selected from the group consisting of asparagine, S-methyl cysteine and the corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, allo-isoleucine, tert-leucine, alanine, phenylalanine, ornithine, histidine, norleucine, glutamine, valine, threonine, allo-threonine, serine, aspartic acid and beta-cyano alanine, side chains;
R2 represents alkylthioalkyl, cycloalkylthioalkyl or arylthioalkyl radicals, which radicals are optionally substituted with a substituent selected from the group consisting of xe2x80x94NO2, xe2x80x94OR15, xe2x80x94SR15, and halogen radicals, wherein R15 represents hydrogen and alkyl radicals;
R3 represents hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl radicals;
Yxe2x80x2 represents O, S and NR3;
R4 and R5 together with the nitrogen atom to which they are bonded represent a N-heterocycle; and R6 represents hydrogen and alkyl radicals.
Another class of preferred inhibitor compounds of the present invention are those represented by the formula: 
or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein:
Rxe2x80x2 represents radicals defined for R3;
t represents either 0 or 1;
R1 represents hydrogen, xe2x80x94CH2SO2NH2, xe2x80x94CO2CH3, xe2x80x94CH2CO2CH3, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, xe2x80x94C(O)N(CH3)2, xe2x80x94CH2C(O)NHCH3, xe2x80x94CH2C(O)N(CH3)2, alkyl, alkylthioalkyl, thioalkyl and the corresponding sulfoxide and sulfone derivatives thereof, alkenyl, alkynyl, alkoxyalkyl, haloalkyl and cycloalkyl radicals and amino acid side chains selected from the group consisting of asparagine, S-methyl cysteine and the corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, allo-isoleucine, tert-leucine, alanine, phenylalanine, ornithine, histidine, norleucine, glutamine, valine, threonine, allo-threonine, serine, aspartic acid and beta-cyano alanine side chains;
R2 represents alkylthioalkyl, cycloalkylthioalkyl or arylthioalkyl radicals, which radicals are optionally substituted with a substituent selected from the group consisting of xe2x80x94NO2, xe2x80x94OR15, xe2x80x94SR15, and halogen radicals, wherein R15 represents hydrogen and alkyl radicals;
R3 represents hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocyclqalkylalkyl, aryl, aralkyl, and heteroaralkyl radicals;
Yxe2x80x2 represents O, S and NR3;
R4 and R5 together with the nitrogen atom to which they are bonded represent a N-heterocycle;
R6 represents hydrogen and alkyl radicals;
and R20 and R21 represent radicals as defined for R1.
Yet another preferred class of compounds of the present invention are those represented by the formula: 
or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein:
t represents either 0 or 1;
R1 represents hydrogen, xe2x80x94CH2SO2NH2, xe2x80x94CO2CH3, xe2x80x94CH2CO2CH3, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, xe2x80x94C(O)N(CH3)2, xe2x80x94CH2C(O)NHCH3, CH2C(O)N(CH3)2, alkyl, thioalkyl, thioalkyl and the corresponding sulfoxide and sulfone derivatives thereof, alkenyl, alkynyl, alkoxyalkyl, haloalkyl and cycloalkyl radicals and amino acid side chains selected from the group consisting of asparagine, S-methyl cysteine and the corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, allo-isoleucine, tert-leucine, alanine, phenylalanine, ornithine, histidine, norleucine, glutamine, valine, threonine, allo-threonine, serine, aspartic acid and beta-cyano alanine side chains;
R2 represents alkylthioalkyl, cycloalkylthioalkyl, or arylthioalkyl radicals, which radicals are optionally substituted with a substituent selected from the group consisting of xe2x80x94NO2, xe2x80x94OR15, xe2x80x94SR15, and halogen radicals, wherein R15 represents hydrogen and alkyl radicals;
R3 represents hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl radicals;
Xxe2x80x2 represent O, N and C(R17) where R17 represents hydrogen and alkyl radicals; Yxe2x80x2 and Yxe2x80x3 independently represent O, S and NR3;
R4 and R5 together with the nitrogen atom to which they are bonded represent a N-heterocycle;
R6 represents hydrogen and alkyl radicals;
R30, R31 and R32 independently represent radicals as defined for R1, or one of R1 and R30 together with one of R31 and R32 and the carbon atoms to which they are attached form a cycloalkyl radical; and
R33 and R34 independently represent radicals as defined for R3, or R33 and R34together with Xxe2x80x2 represent cycloalkyl, aryl, heterocyclyl and heteroaryl radicals, provided that when Xxe2x80x2 is O, R34 is absent.
Still another preferred class of compounds of the present invention are those represented by the formula: 
or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein:
R represents hydrogen, alkoxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbanoyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocycloxycarbonyl, heteroaralkoxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aralkylaminoalkylcarbonyl, aminoalkanoyl, aminocarbonyl, aminocarbonylalkyl, alkylaminoalkylcarbonyl, and mono- and disubstituted aminocarbonyl and aminoalkanoyl radicals wherein the substituents are selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of disubstituted aminoalkanoyl, said substituents along with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl radical;
Rxe2x80x2 represents radicals defined for R3, or R and Rxe2x80x2 together with the nitrogen to which they are attached form a heterocycloalkyl or heteroaryl radical;
n represents 1 or 2;
R1 represents hydrogen, xe2x80x94CH2SO2NH2, xe2x80x94CO2CH3, xe2x80x94CH2CO2CH3, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, xe2x80x94C(O)N(CH3)2, xe2x80x94CH2C(O)NHCH3, xe2x80x94CH2C(O)N(CH3)2, alkyl, alkylthioalkyl, thioalkyl and the corresponding sulfoxide and sulfone derivatives thereof, alkenyl, alkynyl, haloalkyl, alkoxyalkyl and cycloalkyl radicals and amino acid side chains selected from the group consisting of asparagine, S-methyl cysteine and the corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, allo-isoleucine, tert-leucine, alanine, phenylalanine, ornithine, histidine, norleucine, glutamine, valine, threonine, allo-threonine, serine, aspartic acid and beta-cyano alanine side chains;
R1xe2x80x2 and R1xe2x80x3 independently represent hydrogen and radicals as defined for R3;
R2 represents alkylthioalkyl, cycloalkylthioalkyl, or arylthioalkyl radicals, which radicals are optionally substituted with a substituent selected from the group consisting of xe2x80x94NO2, xe2x80x94OR15, xe2x80x94SR15, and halogen radicals, wherein R15 represents hydrogen and alkyl radicals;
R3 represents hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl radicals;
Yxe2x80x2 and Yxe2x80x3 independently represent O, S and NR3;
R4 and R5 together with the nitrogen atom to which they are bonded represent a N-heterocycle;
R6 and R6xe2x80x2 independently represent hydrogen and alkyl radicals.
Another class of preferred inhibitor compounds of the present invention are those represented by the formula: 
or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein:
Rxe2x80x2 represents radicals defined for R3, or R and Rxe2x80x2 together with the nitrogen to which they are attached form a heterocycloalkyl or heteroaryl radical;
t represents either 0 or 1;
R1 represents hydrogen, xe2x80x94CH2SO2NH2, xe2x80x94CO2CH3, xe2x80x94CH2CO2CH3, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, xe2x80x94C(O)N(CH3)2, xe2x80x94CH2C(O)NHCH3, xe2x80x94CH2C(O)N(CH3)2, alkyl, alkylthioalkyl, thioalkyl and the corresponding sulfoxide and sulfone derivatives thereof, alkenyl, alkynyl and cycloalkyl radicals and amino acid side chains selected from the group consisting of asparagine, S-methyl cysteine and the corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, allo-isoleucine, tert-leucine, alanine, phenylalanine, ornithine, histidine, norleucine, glutamine, valine, threonine, allo-threonine, serine, aspartic acid and beta-cyano alanine side chains;
R2 represents alkylthioalkyl, cycloalkylthioalkyl or arylthioalkyl radicals, which radicals are optionally substituted with a substituent selected from the group consisting of xe2x80x94NO2, xe2x80x94OR15, xe2x80x94SR15, and halogen radicals, wherein R15 represents hydrogen and alkyl radicals;
R3 represents hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl radicals;
Yxe2x80x2 represents O, S and NR3;
R4 and R5 together with the nitrogen atom to which they are bonded represent a N-heterocycle;
R6 represents hydrogen and alkyl radicals;
R33 and R34 independently represent radicals as defined for R3, or R33 and R34 together with the nitrogen to which they are attached form heterocyclyl and heteroaryl radicals;
and R20 and R21 represent radicals as defined for R1.
As utilized herein, the term xe2x80x9calkylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain alkyl radical containing from 1 to about 10, preferably from 1 to about 8, carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. The term xe2x80x9cthioalkylxe2x80x9d means an alkyl radical having at least one sulfur atom, wherein alkyl has the significance given above. An example of a thioalkyl is xe2x80x94C(CH3)2SCH3. The corresponding sulfoxide and sulfone of this thioalkyl are xe2x80x94C(CH3)2S(O)CH3 and (CH3)2S(O)2CH3, respectively. The term xe2x80x9calkenylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain hydrocarbon radial having one or more double bonds and containing from 2 to about 18 carbon atoms preferably from 2 to about 8 carbon atoms. Examples of suitable alkenyl radicals include ethenyl, propenyl, allyl, 1,4-butadienyl and the like. The term xe2x80x9calkynylxe2x80x9d, alone or in combination, means a straight-chain hydrocarbon radical having one or more triple bonds and containing from 2 to about 10 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl (propargyl), butynyl and the like. The term xe2x80x9calkoxyxe2x80x9d, alone or in combination, means an allyl ether radical wherein the term alkyl is as defined above. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like. The term xe2x80x9ccycloalkylxe2x80x9d, alone or in combination, means an alkyl radical which contains from about 3 to about 8 carbon atoms and is cyclic.
Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term xe2x80x9ccycloalkylalkylxe2x80x9d means an alkyl radical as defined above which is substituted by a cycloalkyl radical containing from about 3 to about 8, preferably from about 3 to about 6, carbon atoms. The term xe2x80x9carylxe2x80x9d, alone or in combination, means a phenyl or naphthyl radical which optionally carries one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro and the like, such as phenyl (C6H5xe2x80x94), p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 2-hydroxyphenyl, 4-nitrophenyl, 2-nitrophenyl, 1-naphthyl, 2-naphthyl, and the like. The term xe2x80x9caralkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl and the like. The term xe2x80x9caralkoxy carbonylxe2x80x9d, alone or in combination, means a radical of the formula xe2x80x94C(xe2x95x90O)xe2x80x94O-aralkyl in which the term xe2x80x9caralkylxe2x80x9d has the significance given above. An example of an aralkoxycarbonyl radical is benzyloxycarbonyl. The term xe2x80x9caryloxyxe2x80x9d, alone or in combination, means a radical of the formula aryl-Oxe2x80x94 in which the term xe2x80x9carylxe2x80x9d has the significance given above. The term xe2x80x9calkanoyl, alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like. The term xe2x80x9ccycloalkylcarbonylxe2x80x9d means an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from a benz-fused monocyclic cycloalknecarboxylic acid which is optionally substituted by, for example, alkanoylamino, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The term xe2x80x9caralkanoylxe2x80x9d means an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl, and the like. The term xe2x80x9caroylxe2x80x9d means an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals include aromatic. carboxylic acids, an optionally substituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2-naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like. The term xe2x80x9carylthioalkylxe2x80x9d (aryl-S-alkyl) means an aryl radical as defined above attached to a sulfur atom that is attached to an alkyl radical as is defined above and with the preferred alkyl group being 1 to 3 carbon atoms inclusive and the preferred aryl ring being 6 to 10 carbon atoms inclusive and with the oxidation states of sulfur including the sulfide (xe2x80x94Sxe2x80x94), sulfoxide (xe2x80x94S(O)xe2x80x94), or sulfone(xe2x80x94S(O)2)xe2x80x94), with the preferred oxidation state of the sulfur being that of the sulfide (xe2x80x94Sxe2x80x94). Most preferred is an aryl ring of 6 carbon atoms. The term xe2x80x9calkylthioalkylxe2x80x9d means an alkyl group of 1 to 6 carbon atoms inclusive bonded to a sulfur atom witch is bonded to an alkyl group of 1 to 3 carbon atoms inclusive. The heterocyclyl or heterocycloalkyl portion of a heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, or heterocyclylalkyl group or the like is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle which contains one or more hetero atoms selected from nitrogen, oxygen and sulphur, which is optionally substituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo, and the like, and/or on a secondary nitrogen atom (i.e., xe2x80x94NHxe2x80x94) by alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiary nitrogen atom (i.e. xe2x95x90Nxe2x80x94) by oxido and which is attached via a carbon atom. The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl, or heteroaralkoxycarbonyl group or the like is an aromatic monocyclic, bicyclic, or tricyclic heterocyle which contains the hetero atoms and is optionally substituted as defined above with respect to the definition of heterocyclyl. Examples of such heterocyclyl and heteroaryl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol-4-yl, 1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, tetrahydrothienyl, thienyl, triazolyl, oxazolyl, thiazolyl, indolyl (e.g., 2-indolyl, etc.), quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, etc.), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, etc.), tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydro-2-quinolinyl, etc.), 1,2,3,4-tetrahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxalinyl, ,beta-carbolinyl, 2-benzofurancarbonyl, 1-, 2-, 4- or 5-benzimidazolyl, benzofuryl, tetrahydrobenzofuryl and the like. Heteroaryl or heterocycyl (heterocyclo, heterocycle) groups may be bonded through a heteroatom or carbon. The term xe2x80x9ccycloalkylalkoxycarbonylxe2x80x9d means an acyl group derived from a cycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-Oxe2x80x94COxe2x80x94OH wherein cycloalkylalkyl has the significance given above. The term xe2x80x9caryloxyalkanoylxe2x80x9d means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the significance given above. The term xe2x80x9cheterocyclylalkanoylxe2x80x9d is an acyl radical derived from a heterocyclyl-substituted alkane carboxylic acid wherein heterocyclyl has the significance given above. The term xe2x80x9cheterocyclyloxycarbonylxe2x80x9d means an acyl group derived from heterocyclyl-Oxe2x80x94COxe2x80x94OH wherein heterocyclyl is as defined above. The term xe2x80x9cheterocyclylalkanoylxe2x80x9d means an acyl radical of the formula heterocyclyl-alkanoyl wherein heterocyclyl and alkanoyl have the significance given above. The term xe2x80x9cheterocyclylalkoxycarbonylxe2x80x9d means an acyl radical derived from heterocyclyl-substituted alkane-Oxe2x80x94COxe2x80x94OH wherein heterocyclyl has the significance given above. The term xe2x80x9cheteroaryloxycarbonylxe2x80x9d means an acyl radical derived from a carboxylic acid represented by heteroaryl-Oxe2x80x94COOH wherein heteroaryl has the significance given above. The term xe2x80x9caminocarbonylxe2x80x9d alone or in combination, means an amino-substituted carbonyl (carbamoyl) group derived from an amino-substituted carboxylic acid (carbamic acid) Nxe2x80x94(Cxe2x95x90O)xe2x80x94 wherein the amino group can be a primary, secondary or tertiary amino group containing substituents selected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like. The term xe2x80x9caminoalkanoylxe2x80x9d means an acyl radical derived from an amino substituted alkanecarboxylic acid wherein the amino group can be a primary, secondary or tertiary amino group containing substituents selected from the group consisting of hydrogen, cycloalkyl, cycloalkylalkyl radicals and the like, examples of which include N-methylaminoacetyl, N-cyclopropylaminoacetyl, N-methoxyethylaminoacetyl, pyrrolidinyacetyl, N,N-dimethylaminoacetyl and N-benzylaminoacetyl. The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine. The term haloalkyl means an alkyl group substituted with one or more halogen atoms on one or different carbons such as chloromethyl, chlorobromoethyl, trifluoromethyl, 2,2,2-trifluoromethylethylene and the like. The term xe2x80x9cleaving groupxe2x80x9d generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known and include carboxylates, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates, xe2x80x94OR and xe2x80x94SR and the like. Preferred leaving groups are indicated herein where appropriate. The term hydroxypropylenediamine means hydroxyethylamine when applied to this class of protease inhibitors. The term xe2x80x9cN-heterocyclic moietyxe2x80x9d or N-heterocycle is a heterocyclic radical or heterocycle bonded via its nitrogen or with a nitrogen atom radical bond site which may be a heterocycloalkyl or heteroaryl, wherein heterocycloalkyl and heteroaryl have the significance given above, with the addition that polycyclic heteroaryl may be fully aromatic or partially aromatic, for example, a fused heterocycloalkylaryl and a fused heteroarylcycloalkyl, and the heterocycloalkyl and cycloalkyl may also be bridged. Preferably, the N-heterocyclic moiety has 5, 6 or 7 members when monocyclic; 5, 6 or 7 members in a ring with 1, 2 or 3 members in a bridge when a bridged monocyclic; 11, 12 or 13 members when bicyclic; and 11 to 16 members when tricyclic. Examples of N-heterocyclic moieties include, but are not limited to, those represented by the following formulae: 
wherein:
R9 represents hydrogen, alkyl, alkoxycarbonyl, monoalkylcarbamoyl, monoaralkylcarbamoyl, monoarylcarbamoyl or a group of the formula: 
R10 and R11 each represents alkyl;
R12 represents hydrogen, hydroxy, alkoxycarbonylamino or acylamino;
R13 represents hydrogen, alkyl, aryl, alkoxycarbonyl or acyl;
m is 1, 2, 3, or 4;
p is 1 or 2; and
q is 0, 1 or 2.
The term prodrug means esters and amide derivatives of amines, acids, alcohols, thiols and the like that are able to be converted in vitro or in vivo by chemical or biochemical or metabolic processed into an active parent compound. A prodrug may or may not have intrinsic biological activity.
Procedures for preparing the compounds of Formulas I-IV are set forth below. It should be noted that the general procedures are shown as it relates to preparation of compounds having a specified stereochemistry, for example, wherein the stereochemistry about the hydroxyl group is designated as (R). However, such procedures are generally applicable to those compounds of opposite configuration, e.g., where the stereochemistry about the hydroxyl group is (S) or (RS). The terms (R) and (S) configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30. The documents WO 95/09843, U.S. Pat. No. 5,484,926, Kaldor, Stephen W., xe2x80x9cA systematic Study of P1-P3 Spanning Sidechains for the Inhibition of HIV-1 Proteasexe2x80x9d, Bioorganic and Medicinal Chemistry Letters, 5, 715-720 (1995), WO 96/28463, WO 96/28418, WO 96/28465, WO 96/22287, EP 0 346 847, U.S. Pat. No. 5,648,364, WO 96/28464, U.S. Pat. No. 5,521,219, U.S. Pat. No. 5,463,104, U.S. Pat. No. 5,843,946, U.S. Pat. No. 5,756,533, U.S. Pat. No. 5,776,971 and U.S. Pat. No. 5,705,500 include supplementary or alternative methods for preparing intermediates or compounds useful or possibly useful for preparing compounds of this invention as required or desired by a person of ordinary skill in the art which documents are incorporated herein by reference.
The compounds of the present invention represented by formula I through IV above wherein R2 is alkylthioalkyl or arylthioalkyl (ArSCH2xe2x80x94) can be prepared utilizing the following general procedures as illustrated in some cases with compounds wherein R2 is arylalkyl. An N-protected haloketone derivative of an amino acid having the formula: 
wherein P represents an amino protecting group, R2 is as defined above and Z represents a chlorine, bromine or iodine atom, is reduced to the corresponding alcohol utilizing an appropriate reducing agent. Suitable amino protecting groups are well known in the art and include carbobenzoxy, butyryl, t-butoxycarbonyl, acetyl, benzoyl and the like. Preferred amino protecting groups are carbobenzoxy and t-butoxycarbonyl. A preferred N-protected haloketone is a compound of Formula VIII wherein P is benzyloxycarbonyl (Z or CBZ), R2 is phenylthioalkyl and the alkyl group has one carbon atom. A preferred reducing agent is sodium borohydride. The reduction reaction is conducted at a temperature of from xe2x88x9210xc2x0 C. to about 25xc2x0 C., preferably at about 0xc2x0 C., in a suitable solvent system such as, for example, tetrahydrofuran, and the like. The N-protected haloketones may be commercially available from Bachem, Inc., Torrance, Calif. Alternatively, the haloketones can be prepared by the procedure set forth in S. J. Pittkau, J. Prakt. Chem., 315, 1037 (1973), and subsequently N-protected utilizing procedures which are well known in the art.
The resulting alcohol is then reacted, preferably at room temperature, with a suitable base in a suitable solvent system to produce an N-protected amino epoxide of the formula: 
wherein P and R2 are as defined above. Suitable solvent systems for preparing the amino epoxide include methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, and the like including mixtures thereof. Suitable bases for producing the epoxide from the reduced haloketone include potassium hydroxide, sodium hydroxide, potassium t-butoxide, DBU and the like. A preferred base is potassium hydroxide.
Alternatively, a protected amino epoxide can be prepared starting with an D, L or DL-amino acid (illustrated below with an L-aminoacid) which is reacted with a suitable amino- and carboxyl-protecting groups in a suitable solvent to produce an amino-protected L-amino acid ester of the formula: 
wherein P1 and P2 independently represent hydrogen and amino-protecting groups as defined above with respect to P, provided that P1 and P2 are not both hydrogen: P4 represents hydrogen and a carboxy-protecting group, preferably one which is also an amino-protecting group as defined above with respect to P; and R2 is as defined above.
The amino protected L-amino acid ester is then reduced, to the corresponding alcohol. For example, the amino-protected L-amino acid ester can be reduced with diisobutylaluminum hydride at xe2x88x9278xc2x0 C. in a suitable solvent such as toluene. The resulting alcohol is then converted, by way of a Swern Oxidation, to the corresponding aldehyde of the formula: 
wherein P1, p2 and R2 are as defined above. Thus, a dichloromethane solution of the alcohol is added to a cooled (xe2x88x9275 to xe2x88x9268xc2x0 C.) solution of oxalyl chloride in dichloromethane and DMSO in dichloromethane and stirred for 35 minutes.
The aldehyde resulting from the Swern Oxidation is then reacted with a halomethyllithium reagent, which reagent is generated in situ by reacting an alkyl lithium or aryl lithium compound with a dihalomethane represented by the formula X1CH2X2 wherein X1 and x2 independently represent I, Br or Cl. For example, a solution of the aldehyde and chloroiodomethane in THF is cooled to xe2x88x9278xc2x0 C. and a solution of n-butyl lithium in hexane is added. The resulting product is a mixture of diastereomers of the corresponding amino-protected epoxides of the formulas: 
The diastereomers can be separated by chromatography or, alternatively, once reacted in subsequent steps the distereomeric products can be separated.
The amino epoxide is then reacted, in a suitable solvent system, with an equivalent or more amount, of a heterocycle of the formula:
HNR4R5
wherein R4 and R5 are as defined above. The reaction can be conducted over a wide range of temperatures, e.g., from about 60xc2x0 C. to about 120xc2x0 C. in an inert organic solvent, but is preferably, but not necessarily, conducted at a temperature at which the solvent begins to reflux. Suitable solvent systems include those wherein the solvent is an alcohol, such as methanol, ethanol, isopropanol, and the like, ethers such as tetrahydrofuran, dioxane and the like, toluene, N,N-dimethylformamide, dimethylsulfoxide, and mixtures thereof. A preferred solvent is isopropanol. Non-limiting examples of heterocycles corresponding to the formula HNR4R5 include those having the following formula: 
wherein:
R9, R10, R11, R12, R13, m, p and q have the significance given above, and the like. The resulting product is a 3-(N-protected amino)-3-(R2)-1-(NR4R5)-propan-2-ol derivative (hereinafter referred to as an amino alcohol) is an intermediate which contains the desired N-heterocyclic moiety or intermediate thereof and can be represented by the formula: 
wherein p1, p2, R2, R4 and R5 are as described above.
Alternatively, the compounds of the present invention represented by Formula I above can be prepared utilizing the following general procedure. An N-protected haloketone derivative of an amino acid having the formula: 
wherein P, P1 and P2 represent amino protecting groups, R2 is as defined above, and Z represents a chlorine, bromine or iodine atom, is reacted, in a suitable inert organic solvent system, with an equal or greater equivalent amount, of a desired amine of the formula:
HNR4R5
wherein R4 and R5 are as defined above. The reaction yields a compound of the general formula: 
wherein p1, p2, R2, R4 and R5 have the significance given earlier.
The reaction of the N-protected haloketone derivative of an amino acid, preferably-one in which one of pl and/or p2 represent benzyloxy carbonyl and one of P1 and/or p2 represent hydrogen, with the desired amine, a heterocyclic compound of formula HNR4R5, can be carried out in any known manner, for example, in an inert organic solvent such as halogenated aliphatic hydrocarbon (e.g. dichloromethane, N,N-dimethylformamide, tetrahydrofuran, isopropanol and ethanol) and in the presence of a base (e.g. a trialkylamine such as triethylamine and diisopropylethyl amine, sodium bicarbonate, DBU and the like), conveniently at about room temperature.
The reduction of the aminoketone compound of Formula V results in a compound of the general formula: 
wherein p1, p2, R2, R4 and R5 have the significance given earlier. The reduction of the aminoketone compound of Formula V to the N-heterocyclic moiety-containing derivative (Formula VI) can be carried out according to known methods for the reduction of a carbonyl group to a hydroxy group. Thus, for example, the reduction can be carried out using a complex metal hydride such as an alkali metal borohydride, especially sodium borohydride, in an appropriate organic solvent such as alkanol (e.g. methanol, ethanol, propanol, isopropanol etc.).
Conveniently, the reduction is carried out at about room temperature.
Following preparation of the N-heterocyclic moiety-containing derivative, the amino protecting group P is, or P1 and p2 are, removed under conditions which will not affect the remaining-portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of the protecting group, e.g., removal of a carbobenzoxy group, by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. Where the protecting group is N,N-dibenzyl, these groups may be removed by hydrogenolysis utilizing palladium on carbon. Where the protecting group is a t-butoxycarbonyl group, it can be removed utilizing an inorganic or organic acid, e.g., HCl or trifluoroacetic acid, in a suitable solvent system, e.g., dioxane or methylene chloride. The resulting product is the amine salt derivative. Following neutralization of the salt, the amine is then reacted with an amino acid or corresponding derivative thereof represented by the formula (RR1NCH(R1)COOH) or (RR1N[CR1xe2x80x2R1xe2x80x3]CH(R1)COOH) wherein R1xe2x80x2, R1xe2x80x3 and R1 are as defined above and may be P and/or P1 and/or P2 to produce the antiviral compounds of the present invention having the formula: 
or 
wherein P, R1, R1xe2x80x2, R1xe2x80x3, R2, R4 and R5 are as def ined above.
Preferred protecting groups in this instance are a benzyloxycarbonyl group or a t-butoxycarbonyl group. Where the amine is reacted with a derivative of an amino acid and R1xe2x80x2 and R1xe2x80x3 are both hydrogen, so that the amino acid is a, beta-amino acid, such, beta-amino acids can be prepared according to the procedure set forth in copending applications, U.S. Ser. No. 07/836,163 Method of Preparing Optically Active, beta-Amino Acids; filed Feb. 14, 1992; Docket No. 07-21(855)A) (a continuation of U.S. Ser. No. 07/706,508, now abandoned, which is a continuation of U.S. Ser. No. 07/345,808, now abandoned). Where one of R1xe2x80x2 and R1xe2x80x3 is hydrogen and R1 is hydrogen so that the amino acid is a homo-beta-amino acid, such homo-beta-amino acids can be prepared according to the procedure set forth in copending application, U.S. Ser. No. 07/853,561 (Method of Preparing Optically Active Homo-beta-Amino Acids; filed; Docket No. 07-21(722)A). The process thereof preserves the chirality of the starting succinates. The method thereof involves Curtis rearrangement of chiral 3-mono-substituted succinates (succinic acid half ester) of sufficient purity to exhibit optical activity. The Curtis rearrangement is preferably effected by treating a chiral 3-mono-substituted succinate with one equivalent of diphenoxyphosphoryl azide (PhO)2PON3 and triethylamine to form an acyl azide followed by heating in an inert solvent, such as warm toluene, preferably at about 80xc2x0 C. for about three hours to afford an isocyanate derivative which is subsequently hydrolyzed to give amines. The 3-mono-substituted succinates can be prepared by a procedure analogous to that described in U.S. Pat. No. 4,939,288, filed Jan. 23, 1989, which is hereby incorporated by reference. The alpha-amino acid compounds are prepared using, for example, methods in U.S. Pat. No. 5,483,946, or variations well know in the art. It should be noted that compounds of this invention can be prepared in stepwise as is shown by the example in Scheme 1 and Scheme 2 herein below or via a convergent synthesis where parts of the final product are made separately and coupled in a final step to produce said final product of this invention. The person skilled in the art will select the appropriate process based on compound to be made under particular conditions at that particular time or location. 
Coupling conditions such as mixed anhydride reaction, activated ester coupling with, for example, hydroxybenzotriazol (HOBT) and the like are very well know in the art especially the aminoacid and peptide synthesis and reaction art.
The N-protecting group can be subsequently removed, if desired, utilizing the procedures described above, and then reacted with a carboxylate represented by the formula: 
wherein R is as defined above and L is an appropriate leaving group such as a halide. Examples of such carboxylates include acetylchloride, phenoxyacetyl chloride, benzoyl chloride, 2-naphthyloxycarbonyl chloride and 2-benzofurancarbonyl chloride. A solution of the free amine (or amine acetate salt) and about 1.0 equivalent of the carboxylate are mixed in an appropriate solvent system and optionally treated with up to five equivalents of a base such as, for example, N-methylmorpholine, at about room temperature. Appropriate solvent systems include tetrahydrofuran, methylene chloride or N,N-dimethylformamide, and the like, including mixtures thereof.
Alternatively, a sulfonyl-containing compound represented by the formula: 
wherein R is as defined above and L is an appropriate leaving group such as halide may be substituted for the aforementioned carboxylate.
A mercaptan of the formula Rxe2x80x2SH is reacted with a substituted methacrylate of the formula: 
by way of a Michael Addition. The Michael Addition is conducted in a suitable solvent and in the presence of a suitable base, to produce the corresponding thiol derivative represented by the formula: 
wherein Rxe2x80x2 and R1 represent radicals defined above; R20 and R21 represent hydrogen and radicals as defined for R1; and R22 represents alkyl, aryl or aralkyl, preferably R22 is methyl, ethyl, t-butyl or benzyl. Suitable solvents in which the Michael Addition can be conducted include alcohols such as, for example, methanol, ethanol, butanol and the like, as well as ethers, e.g., THF, and acetonitrile, DMF, DMSO, and the like, including mixtures thereof. Suitable bases include Group I metal alkoxides such as, for example sodium methoxide, sodium ethoxide, sodium butoxide and the like as well as Group I metal hydrides, such as sodium hydride, including mixtures thereof.
The thiol derivative is converted into the corresponding sulfone of the formula: 
by oxidizing the thiol derivative with a suitable oxidation agent in a suitable solvent. Suitable oxidation agents include, for example, hydrogen peroxide, sodium meta-perborate, potassium peroxy monosulfate, meta-chloroperoxybenzeic acid, and the like, including mixtures thereof. Suitable solvents include acetic acid (for sodium meta-perborate) and, for other peracids, ethers such as THP and dioxane, and acetonitrile, DME and the like, including mixtures thereof.
The sulfone is then converted to the corresponding free acid of the formula: 
utilizing a suitable base, e.g., lithium hydroxide, sodium hydroxide, and the like, including mixtures thereof, in a suitable solvent, such as, for example, THF, acetonitrile, DMF, DMSO, methylene chloride and the like, including mixtures thereof. When R22 is benzyl, the free acid may be obtained by hydrogenolysis over palladium on carbon.
The free acid is then coupled, utilizing, as described above, procedures well known in the art, to the N-heterocyclic moiety-containing derivative of an amino alcohol which is described above for the preparation of compounds of Formula I. The resulting product is a compound represented by Formula II.
Alternatively, one can couple the N-heterocyclic moiety-containing derivative to the commercially available acid, 
remove the thioacetyl group with a suitable base, such as hydroxide, or an amine, or ammonia, and then react the resulting thiol with an alkylating agent, such as an alkyl halide, tosylate or mesylate to afford compounds at the following structure: 
The sulfur can then be oxidized to the corresponding sulfone using suitable oxidizing agents, as described above, to afford the desired compounds of the following structure: 
Alternatively, to prepare compounds of Formula II, a substituted methacrylate of the formula: 
wherein L represents a leaving group as previously defined, R35 and R36 represent hydrogen and radicals as defined for R1; and R37 represents alkyl, aralkyl, cycloalkyl and cycloalkylalkyl radicals, is reacted with a suitable sulfonating agent, such as, for example, a sulfinic acid represented by the formula Rxe2x80x2SO2M, wherein Rxe2x80x2 represents radicals as defined above and M represents a metal adapted to form a salt of the acid, e.g., sodium, to produce the corresponding sulfone represented by the formula: 
wherein Rxe2x80x2, R35, R36 and R37 are as defined above. The sulfone is then hydrolyzed in the presence of a suitable base, such as lithium hydroxide, sodium hydroxide and the like, to the compound represented by the formula: 
wherein Rxe2x80x2, R35 and R36 represent radicals as defined above. The resulting compound is then asymmetrically hydrogenated utilizing an asymmetric hydrogenation such as, for example, a ruthenium-BINAP complex to produce the reduced product, substantially enriched in the more active isomer represented by the formula: 
wherein Rxe2x80x2, R35 and R36 represent radicals as defined above. Where the more active isomer has the R-stereochemistry, a Ru(R-BINAP) asymmetric hydrogenation catalyst can be utilized. Conversely, where the more active isomer has the S-stereochemistry, a Ru(S-BINAP) catalyst can be utilized. Where both isomers are active, or where it is desired to have a mixture of the two diastereomers, a hydrogenation catalyst such as platinum, or palladium on carbon can be utilized to reduce the above compound. The reduced compound is then coupled to the N-heterocyclic moiety-containing derivative, as described above, to produce compounds of Formula II.
Alternatively, one can prepare the preferred 2(S)-methyl-3-(methylsulfonyl)propionic acid according to the scheme outlined below starting from commercially available D-(xe2x88x92)-S-benzyoyl-beta-mercaptoisobutyric acid tert-butyl ester. Treatment of D-(xe2x88x92)-S-benzoyl-beta-mercaptoisobutyric acid tert-butyl ester with a methanolic ammonia solution resulted in the formation of D-(xe2x88x92)-beta-mercaptoisobutyric acid tert-butyl ester and benzamide. The free mercaptan thus produced was freed from the benzamide by filtration and then further purified by crystallization. Treatment of D-(xe2x88x92)-beta-mercaptoisobutyric acid tert-butyl ester with methyl iodide in the presence of a suitable base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) results in the formation of the corresponding thioether S-methyl-D-(xe2x88x92)-beta-mercaptoisobutyric acid tert-butylester in excellent yield. The thioether is then oxidized with a suitable oxidant such as sodium metaperborate in acetic acid to give the corresponding sulfone. Specifically, S-methyl-D-(xe2x88x92)-beta-mercaptoisobutyric acid tert-butyl ester is treated with sodium perborate in acetic acid to produce 2(S)-methyl-3-(methylsulfonyl)propionic acid tert-butyl ester in excellent yield. The tert-butyl ester can then selectively removed by treatment with 4N hydrochloric acid in dioxane to produce 2(S)-methyl-3-(methylsulfonyl)propionic acid as a crystalline acid in very good yield. It is envisioned that variations of the sulfur and carboxylate protecting groups would be acceptable for preparation of 2(S)-methyl-3-(methylsulfonyl)propionic acid and analogs. 
To produce compounds of Formula III, starting with a lactate of formula: 
wherein Pxe2x80x3 represents alkyl and aralkyl radicals, such as, for example, ethyl, methyl, benzyl and the like. The hydroxyl group of the lactate is protected as its ketal by reaction in a suitable solvent system with methyl isopropenyl ether (1,2-methoxypropene) in the presence of a suitable acid. Suitable solvent systems include methylene chloride, tetrahydrofuran and the like as well as mixtures thereof. Suitable acids include POCl3 and the like. It should be noted that well-known groups other than methyl isopropenyl ether can be utilized to form the ketal. The ketal is then reduced with diisobutyhluminum hydride (DIBAL) at xe2x88x9278xc2x0 C. to produce the corresponding aldehyde which is then treated with ethylidenetriphenylphosphorane (Wittig reaction) to produce a compound represented by the formula: 
The ketal protecting group is then removed utilizing procedures well-known in the art such as by mild acid hydrolysis. The resulting compound is then esterified with isobutyryl chloride to produce a compound of the formula: 
This compound is then treated with lithium diisopropyl amide at xe2x88x9278xc2x0 C. followed by warming of the reaction mixture to room temperature to effect a Claisen rearrangement ([3,3]) to produce the corresponding acid represented by the formula: 
Treatment of the acid with benzyl bromide (BnBr) in the presence of a tertiary amine base, e.g., DBU, produces the corresponding ester which is then cleaved oxidatively to give a trisubstituted succinic acid: 
The trisubstituted succinic acid is then coupled to the N-heterocyclic moiety-containing derivative as described above. To produce the free acid, the benzyl ester is removed by hydrogenolysis to produce the corresponding acid. The acid can then be converted to the primary amide by methods well-known in the art.
An alternative method for preparing trisubstituted succinic acids involves reacting an ester of acetoacetic acid represented by the formula: 
where R is a suitable protecting group, such as methyl, ethyl, benzyl or t-butyl with sodium hydride and a hydrocarbyl halide (R31X or R32X) in a suitable solvent, e.g., THF, to produce the corresponding disubstituted derivative represented by the formula: 
This disubstituted acetoacetic acid derivative is then treated with lithium diisopropyl amide at about xe2x88x9210xc2x0 C. and in the presence of PhN(triflate)2 to produce a vinyl triflate of the formula: 
The vinyl triflate is then carbonylated utilizing a palladium catalyst, e.g., Pd(OAc)2(Ph3)P, in the presence of an alcohol (Rxe2x80x3OH) or water (Rxe2x80x3=H) and a base, e.g., triethylamine, in a suitable solvent such as DMF, to produce the olefinic ester or acid of the formula: 
The olefin can then be subsequently asymmetrically hydrogenated, as described above, to produce a trisubstituted succinic acid derivative of the formula: 
If Rxe2x80x3 is not H, Rxe2x80x3 can be removed by either hydrolysis, acidolysis, or hydrogenolysis, to afford the corresponding acid, which is then coupled to the N-heterocyclic moiety-containing derivative as described above and then, optionally, the R group removed to produce the corresponding acid, and optionally, converted to the amide.
Alternatively, one can react the N-heterocyclic moiety-containing derivative with either a suitably monoprotected succinic acid or glutaric acid of the following structures; 
followed by removal of the protecting group and conversion of the resulting acid to an amide. One can also react an anhydride of the following-structure: 
with the N-heterocyclic moiety-containing derivative and then separate any isomers or convert the resulting acid to an amide and then separate any isomers.
It is contemplated that for preparing compounds of the Formulas having R6 being other than hydrogen, the compounds can be prepared following the procedure set forth above and, prior to coupling the N-heterocyclic moiety-containing derivative to the respective acid, the derivative carried through a procedure referred to in the art as reductive amination. Thus, a sodium cyanoborohydride and an appropriate aldehyde, such as formaldehyde, acetaldehyde and the like, can be reacted with the N-heterocyclic moiety-containing derivative compound at room temperature in order to reductively aminate any of the compounds of Formulas I-IV.
Contemplated equivalents of the respective general formulas set forth above for the antiviral compounds and derivatives as well as the intermediates are compounds otherwise corresponding thereto and having the same general properties wherein one or more of the various R groups are simple variations of the substituents as defined therein, e.g., wherein R is a higher alkyl group than that indicated. In addition, where a substituent is designated as, or can be, a hydrogen, the exact chemical nature of a substituent which is other than hydrogen at that position, e.g., a hydrocarbyl radical or a halogen, hydroxy, amino and the like functional group, is not critical so long as it does not adversely affect the overall activity and/or synthesis procedure.
Optically active compound isomers as well as mixed or non-optically active compound isomers are specifically intended to be included in this discussion and in this invention. Examples of isomers are RS isomers, enantiomers, diastereomers, racemates, cis isomers, trans isomers, E isomers, Z isomers, syn-isomers, anti-isomers, tautomers and the like. Aryl, heterocyclo or heteroaryl tautomers, heteroatom isomers and ortho, meta or para substitution isomers are also included as isomers. Solvates or solvent addition compounds such as hydrates or alcoholates are also specifically included both as chemicals of this invention and in, for example, formulations or pharmaceutical compositions for delivery. In the propylene diamine (hydroxyethylamine) function, a preferred configuration for the carbon bearing hydroxyl is R when the configuration at the carbon bearing the phenylthiomethylene group is R. A preferred set of isomers includes those depicted in the compounds of Examples 21 through 34 inclusive.
The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily preparable from known starting materials.